EP1638909A2

EP1638909A2 - Process for preparing alkoxy- and aryloxy-phenols

Info

Publication number: EP1638909A2
Application number: EP04726167A
Authority: EP
Inventors: Valerio Borzatta; Oreste Piccolo; Elisa Capparella; Elisa Poluzzi
Original assignee: Endura SpA
Current assignee: Endura SpA
Priority date: 2003-04-18
Filing date: 2004-04-07
Publication date: 2006-03-29
Also published as: WO2004092106A2; CN1777572A; CN100467436C; ITMI20030823A1; WO2004092106A3

Abstract

Process for preparing alkoxy- and aryloxy-phenols, comprising oxidizing the ketone of formula (I) with peracids to give the corresponding ester of formula (II) which is then hydrolysed to give the corresponding aryloxy- or alkoxy-phenol.

Description

PROCESS FOR PREPARING ALKOXY- AND ARYLOXY-PHENOLS

FIELD OF THE INVENTION

The present invention relates to a process for preparing alkoxy- and aryloxy- phenols. STATE OF THE ART

Alkoxy- and aryloxy-phenols are products which have wide industrial usage. Among these, for example, sesamol i.e. 3,4-(methylenedioxy)-phenol is a compound used as an intermediate in the preparation of pharmaceutical products and is also used as an antioxidant, as an antibacterial and herbicidal agent and in the cosmetic industry.

Of the synthesis methods, a very frequently used reaction is the Baeyer-Villiger reaction, which uses the corresponding aromatic aldehydes. This reaction involves the transformation of the aldehyde compound to the corresponding phenol formate and its subsequent hydrolysis to give the phenolic compound. Thus in US 5,840,997 the preparation of alkoxy- and aryloxy-phenols is described using the corresponding aldehydes. The oxidation process is conducted in the heterogeneous phase with hydrogen peroxide and formic acid, using dichloromethane as solvent. Patent application EP 1167365 A1 describes a process for the synthesis of sesamol via oxidation of the corresponding piperonyl aldehyde using peracetic acid in the presence of formic acid in an organic solvent.

In Ind. J. Chem. 1983, 22, 1150 the oxidation of aromatic aldehyde compounds to give phenolic derivatives is conducted using m-chloroperbenzoic acid in a chlorinated solvent such as dichloromethane. In SU 688,492 the oxidation of aldehydes is conducted using performic acid in a chlorinated solvent such as dichloromethane.

Oxidation of aromatic ketones to the corresponding phenols has been used almost exclusively for acetophenones and benzophenones, while the higher homologues of the C₂-C₆ aliphatic ketones have not been considered because less selective reactions can normally be obtained with the formation of mixtures of esters (cfr. March, Advanced Organic Chemistry, 5^th Edition, Wiley, p. 1417). J. Am. Chem. Soc. 7-1. 14 (1949) describes the oxidation of certain ketones in chloroform with perbenzoic acid with extremely long reaction times (10 days).

Synthesis, 1989, 167-171, describes the oxidation of acetophenones to phenols using hydrogen peroxide at high concentration (90%) in the presence of selenium compounds as oxidation catalysts. Synthetic Comm. 29(21 ), 3781-3791 (1999) describes the oxidation of aromatic aldehydes, acetophenones and benzophenoπes with hydrogen peroxide, activated by boric acid in the presence of sulphuric acid.

No mention was made regarding the use of aromatic ketones different from acetophenone or benzophenone derivatives. The conditions described are barely applicable due to the high concentration of hydrogen peroxide, the presence of oxidation catalysts, such as boron and selenium, having considerable environmental impact, and the very long reaction times.

Consequently, the skilled in the art in the preparation of alkyloxy- and aryloxy- phenols is prompted to consider the greater advantage of oxidizing the corresponding aromatic aldehydes.

SUMMARY OF THE INVENTION

The applicant has now unexpectedly found that the drawbacks of the known art can be overcome by a process according to the present invention which involves the use of a ketone of formula (I)

(I)

In which Xι, X₂, m, n and R are as indicated hereinafter, in the oxidation reaction with peracids either preformed or prepared in situ by the action of hydrogen peroxide with the corresponding organic acids in an inert solvent. The use of ketones enables non-anhydrous reaction environments to be achieved in that the corresponding esters are not as reactive to acid hydrolysis in contrast to that which occurs with formic esters derived from the oxidation of aldehyde compounds, thus minimizing by-products due to oxidation. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the production of alkoxy- and aryloxy-phenols, starting from a ketone of formula (I) where X_. and X₂, equal or different, are linear or branched Ci-Cs alkyl, preferably C1-C4 alkyl, C₆-Cιo aryl unsubstituted or substituted with C-i-Cβ alkyl, with trifluoromethyl or with halogen, such as chlorine, bromine, iodine and fluorine, or (OXι)n and (OX₂)m, taken together, correspond to the group O-T-O, where T is CH₂, CH₂CH₂ or C(Me)₂ and preferably CH₂; C_β aryl unsubstituted or substituted with Cι-C₂ alkyl is preferred; n and m are 0, 1 , or 2 with the condition that when n = m they are always different from 0; R is linear or branched C₂-Ce alkyl or cyclohexyl, and preferably C₂-C₃ alkyl, more preferably ethyl.

The present invention comprises a process for the conversion of compounds of formula (I), where X₁₍ X₂, n, m and R have the aforestated meaning, which comprises the following stages: a) oxidation of the compound of formula (I) with peracid in an inert organic solvent to give the corresponding ester of formula (II);

(II) where X-i, X₂, n, m and R have the aforestated meaning b) hydrolysis of the ester of formula (II) to give the corresponding phenol of formula (III)

(III) where Xi, X₂₎ n and m have the aforestated meaning. As stated previously, the ketoπe of formula (I) dissolved in an inert solvent is oxidised to the corresponding ester by Baeyer-Villiger oxidation using peracids preformed or generated in situ such as, preferably, performic, peracetic, permaleic, perbenzoic and perphthalic acids. The most preferred is performic acid prepared in situ by the reaction of formic acid with hydrogen peroxide. The amount of formic acid can vary from 1.5 to 8 equivalents per mole of ketone, preferably from 2 to 5 equivalents per mole of ketone. The hydrogen peroxide is used from 1 to 6 equivalents per mole of ketone and preferably from 1.2 to 3 equivalents per mole of ketone.

The inert solvent is an organic solvent immiscible with water and able to dissolve ketones of formula (I) and carboxylic acid or the corresponding peracid.

The inert solvent is chosen from pentaπe, hexaπe, heptane, octane and their mixtures, dichloromethane, chloroform, carbon tetrachloride and dichloroethane.

Chlorinated solvents are preferred. Dichloromethane is particularly preferred.

The volume of solvent per mole of the ketoπe of formula (I) used in stage (a) is between 0.05 litres and 1.5 litres preferably between 0.05 litres and 1 litre, more preferably between 0.2 litres and 0.5 litres.

The hydrogen peroxide used is that commercially available and easy to handle, with a concentration varying between 30% and 35% (% w/v) The formic acid used has a concentration greater than 80% (% w/w), preferably greater or equal to 85% (w/w).

The oxidation reaction is conducted at a temperature between 20° and 80°C, preferably between 30° and 50°C, more preferably between 40° and 50°C. The hydrolysis of the ester of formula (II) can be conducted in a basic or acidic environment.

A basic environment is preferred.

When the hydrolysis reaction is conducted in a basic environment, the base added is an alkaline hydroxide in aqueous solution. Sodium hydroxide is preferred. The base is added in a quantity between 3 and 6 equivalents of sodium hydroxide per mole of ester.

4 molar equivalents of sodium hydroxide per mole of ester are preferred.

The reaction solvent is the same inert solvent used in the reaction of stage (a).

In this case the same reaction mixture derived from stage (a) is used after removing the aqueous phase.

In accordance with a particularly preferred embodiment the hydrolysis reaction in basic environment is conducted in the presence of a phase transfer catalyst, even more preferably with tetrabutylammonium chloride or Aliquat 360.

The phase transfer catalyst is preferably added in a molar ratio between 1/20 and 1/90 per mole of ester of formula (II). A molar ratio between 1/40 and 1/80 per mole of ester is particularly preferred.

The acid hydrolysis reaction is conducted in accordance with the known art, in a

C1-C1₀ alcoholic solvent, preferably in a C₁-C₃ alcohol, more preferably in methanol. The acid used as catalyst is usually a strong mineral acid, preferably 96% (%w/w) concentrated sulphuric acid.

In this case the acid is added in molar ratios between 1% and 2% molar per mole of the ester of formula (II).

The acid hydrolysis reaction is conducted at a temperature between 30° and 60°C, more preferably at 40°C.

The separation of the alkoxy- or aryloxy-phenol of formula (III) coming from acid hydrolysis, conducted in particular with sulphuric acid in accordance with the aforesaid preferred operative conditions is preferably conducted with a procedure comprising the following stages:

A) the methanol is evaporated under reduced pressure;

B) the remainder is re-dissolved with methylene chloride and a solution of sodium hydroxide, preferably 2M, is added; the organic phase containing the ketone and the unreacted ester is removed,

C) the aqueous phase containing the sodium salt of the phenol of formula (III) is acidified with organic mineral acid, preferably 37% HCI, to release the alkyloxy- or the aryloxy-phenol of formula (III) which is extracted with methylene chloride, D) the methylene chloride is evaporated to obtain a residue which is then distilled and/or crystallised to obtain the alkyloxy- or the aryloxy-phenol. The alkyloxy- or the aryloxy-phenol of formula (III) derived from basic hydrolysis is instead separated from the reaction mixture conducted in stage (b) by a procedure comprising the following operative steps: A') the 2 phases are separated from the reaction mixture; the organic phase containing the unreacted ketone, the non-hydrolysed ester and possibly the catalyst is removed, while the aqueous phase is treated in the same manner as in the aforestated (C) and (D) for the product derived from acid catalysis, but in this case stages (B') and (C) are instead defined thus; B') the aqueous phase containing the sodium salt of the alkyloxy- or aryloxy- phenol of formula (III) is acidified with a strong mineral acid, preferably 37% HCI, to release the corresponding phenolic derivative which is extracted with methylene chloride, C) the methylene chloride is evaporated until a residue is obtained which is then distilled and/or crystallised to obtain the alkyloxy- or the aryloxy-phenol derivative of formula (III).

Both the unreacted ketoπe derived from hydrolysis under acid catalysis and that obtained under basic catalysis can be easily recycled in stage (a). In this respect, if the reaction mixture is derived from acid hydrolysis the organic phase of stage (a) is recycled, whereas if the hydrolysis is conducted in a basic environment the organic phase of stage (A') is used for the recycling. In this case the organic phase, as well as the ketone and the non-hydrolysed ester, also contains the phase transfer catalyst.

The applicant has also surprisingly found that by recycling this organic phase containing said phase transfer catalyst, conversion, selectivity and reaction yield of the desired ester can be increased, in addition to which further catalyst need not be added to the subsequent hydrolysis cycle

The ketones particularly preferred for use as starting reagents and the corresponding phenols which can be obtained therefrom with the process of the present invention are given below.

in which Ri is ethyl or n-propyl.

The aforesaid ketones are prepared in accordance with the known art, or are available commercially. Where R is ethyl and O-T-0 is CH₂ in the ketone of 5 formula (I), the latter is prepared as described in US 6,342,613.

The following are illustrative but non-limiting examples of preparation using the process of the present invention.

EXAMPLE 1

Synthesis of sesamyl propanoate (ester (II) with R=ethyl m=1 and Xi and X₂, taken

10 together, correspond to the group 0-T-O, where T is CH₂).

460 g (2.5 moles) of 1 ,3-benzodioxol-5-propan-1-one (ketone of formula (I) in which R=ethyl, m=1 and X. and X , taken together, correspond to the O-T-0 group, where T is CH₂), (purity 96.7%), 650 ml of methylene chloride and 249.6 g (5.3 moles) of formic acid (98%) are fed into a flask, and 339.2( 3.5 moles) g of

15 35% hydrogen peroxide are dropped at a rate of 0.35 g/minute for 6 hours. At the end of the reaction the phases are separated. The aqueous phase is extracted with 130 ml of methylene chloride; the organic phase is washed with 140 g of 10% Na₂Sθ₃ and 130 ml of water to eliminate the peroxides. The phases are separated and the organic phase is evaporated under vacuum at 30°C/23 mbar;

20 yield with respect to the converted ketone =94%.

EXAMPLE 2A - Acid hydrolysis of sesamyl propanoate.

1200 ml of methanol and 3.4 g of 96% sulphuric acid are added to the crude reaction product from example 1. The mixture is stirred at 40°C for 9 hours, then cooled and the solvent is evaporated under vacuum at 30°C/23 mbar.

25 The remainder is re-dissolved in 500 ml of methylene chloride to which 790 ml of 2M sodium hydroxide are added.

The mixture is then stirred for 10 minutes and the phases are separated. The aqueous phase is extracted with 50 ml of methylene chloride. The organic phase containing the ketone and the non-hydrolysed ester is recycled as described in the

30 following example 3A.

The aqueous phase containing the sodium sesamate is then added with 37% HCI till to pH 8.5 to obtain sesamol in free form, which is then extracted with 50 ml of methylene chloride. The organic phase containing the sesamol is concentrated under vacuum at 30°C/23 mbar.

The sesamol is distilled at 116°C/3-4 mbar; hydrolysis yield: 94.3%.

EXAMPLE 2B Basic hydrolysis of sesamyl propanoate 1325 ml of 4M sodium hydroxide and 3.6 g ( 13 mmoles) of 98% hydrated tetrabutylammoπium chloride are added to the organic phase in methylene chloride obtained at the end of the reaction in example 1. After stirring for 8 hours at room temperature, the phases are separated. 200 ml of methylene chloride are added to the aqueous phase, which is added with 37% HCI till to pH 8.5 to release the sesamol which passes into the organic phase. The organic phase is separated and the solvent is evaporated under vacuum at 30°C/23 mbar. The sesamol is distilled at 116°C/23 mbar; hydrolysis yield: 95.8%. EXAMPLE 3A - Recycling of the product derived from acid hydrolysis Following hydrolysis in an acid environment as described in example 2A and then treating with aqueous sodium hydroxide in methylene chloride to cause the sesamol to pass into the aqueous phase as sodium sesamate, the ketone and the non-hydrolyzed ester dissolved in the organic phase are reacted as described in example 1. The ketone is added at the same quantity as in example 1 , using the same reaction conditions and the same quantities of reagents given in example 1. Sesamyl propanoate is obtained with an 85% yield with respect to the converted product.

EXAMPLE 3B - Recycling of the product derived from basic hydrolysis Following hydrolysis in an alkaline environment as described in example 2B, the organic solution containing the unreacted ketoπe and the non-hydrolyzed ester is made up to the same quantity of ketone indicated in example 1 , and reacted as in example 1. The hydrolysis reaction is carried out by the same operative method given in example 3B and using the same molar ratio of sesamyl propaπoate/NaOH, with no further addition of catalyst. After distillation sesamol is obtained with a hydrolysis yield equal to 94%. EXAMPLE 4 - Synthesis of sesamyl propanoate 233.2 g of 1 ,3-benzodioxol-5-propan-1-one(1.25 moles) (purity 96.4%) and 325 ml of CH₂CI₂ are mixed into a 2 litre reactor:

142.1 g (2.62 moles) of 85% HCOOH are then added. The temperature is heated to 47°C and 170.0 g (1.75 moles) of 35% H₂0₂ are added over a 6 hour period (at a rate of 0.47 g/min). After leaving under reflux for 6 hours, the phases are separated at the end of the reaction. The organic phase is washed with 70 g of 10% Na₂S0₃ and 60 ml of water. The organic phase is analysed by GC to obtain a yield with respect to the converted product equal to 94.5%

EXAMPLE 4 A - Basic hydrolysis 2.32 g ( 8 mmoles) of hydrated tetrabutylammonium chloride are added to the previous organic phase and 664 g (2.7 moles) of 4M NaOH are added over 45 minutes while maintaining the temperature at 20-25°C.

After stirring for 8 hours at room temperature the phases are separated.

100 ml of CH₂CI₂ are added to the aqueous phase which is added with 37% HCI till to pH 8.5. The phases are separated. The organic phase containing the sesamol is concentrated under vacuum at 30°C/23 mbar.

The sesamol is distilled at 116°C/3-4 mbar to obtain 82 g of product.

Yield with respect to converted product: 92.3%.

The distilled sesamol is crystallised in a 1/2(v/v) mixture of toluene/cyclohexane. The solid obtained is filtered off and dried under vacuum at 40°C/23 mbar. 79 g of crystallised sesamol with a concentration of 99.7% w/w are obtained.

EXAMPLE 5 -Synthesis of 3,4-dimethoxy-phenol

A mixture of 9.6g (50 mrmol) of 1-(3,4 -dimethoxy-phenyl)-1 propanone , 13 ml of dichloromethane and 5.2g (110mmol) of 95% formic acid are heated to 40°C; then 6.9g (70mmol) of 35% hydrogen peroxide are slowly added.

Once the hydrogen peroxide addition is completed, the mixture is left under reflux for 6 hours. Then the reaction mixture is cooled, the organic phase is separated and washed with 5 ml of an aqueous solution of 10% sodium sulphite(%w/w) and finally with water. Then 0.12g (0.4mmol) of 98% hydrated tetrabutyl ammonium chloride are added to the organic solution. 32 ml of 4M sodium hydroxide are added at room temperature to the mixture under stirring. The reaction mixture is heated under reflux for six hours and thereafter cooled, until obtaining the separation into two distinct phases. 20 ml of dichloromethane are added to the aqueous phase and afterwards 37% HCI up to a pH value of about 1. The organic phase is washed with water dried on sodium sulphate filtered and evaporated at 30°C/24 mbar.

An oil (4.1g) is obtained which is then crystallised from ethanol, thereby obtaining a product having m.p.78-80°C , whose NMR and MS analyses correspond to those of the aforementioned compound. EXAMPLE 6 -Synthesis of 1-4-(phenoxy) phenol Analogously to what described in Example 5 a mixture of 8.7g (38mmol) of 1- (4phenoxyphenyl)-1-propanone, 13 ml of dichloromethane, 4.5g (90mmol) of 95% formic acid are reacted with 6.0g (60 mmol) of 35%hydrogen peroxide. After treatment of the organic solution as described in example 5, 0.09 g (0.32 mmol) of 98% hydrated tetrabutylammonium chloride are added to the reaction mixture, which is then treated with 24 ml of 4M sodium hydroxide.

After an analogous treatment as described in Example 5, 4.1g of a product are obtained which after crystallisation from petroleum ether has m. p. = 83-84°C whose NMR and MS correspond to those of the desired compound . EXAMPLE 7 Synthesis of 3,4-methylendioxy-phenol Analogously to what described in Example 5, a mixture of 10.0g (51mmol) of 1- (1 ,3-benzodioxol-5-yl)1-butanone, 15 ml of dichloromethane, 5.25 g ( 108 mmoles) of 95% formic acid is reacted with 7.0 g (72mmol) of 35% hydrogen peroxide. After treatment of the organic solution as described in Example 5, 0.109 g (0.38mmol) of 98% hydrated tetrabutylammonium chloride are added to the reaction mixture, which is then treated with 31ml of 4M sodium hydroxide. After an analogous treatment as described in Example 5, 3.8 g of a product are obtained which after the crystallisation from a mixture of cyclohexane/dichloromethane, has m.p. 63°-65°C, whose NMR and MS correspond to those of the desired compound.

EXAMPLE 8- Synthesis of 6-hydroxy-2,3dihydro-1 ,4-benzodioxine

Analogously to what described in Example 5, a mixture of 9.42g (49mmol) of 1- (2,3,dihydro-1,4-benzodioxin-6-yl)-1-propanone, 14 ml of dichloromethane, 5.0 g

(100 mmol) of 95% formic acid is reacted with 6.8g (70mmol) of 35% hydrogen peroxide.

After treatment of the organic solution as described in Example 5, 0.09g (0.32 mmol) of 98% hydrated tetrabutylammonium chloride are added to the organic solution and the reaction mixture thus obtained is reacted with 24 ml of 4M sodium hydroxide.

After an analogous treatment to that described in example 5, an oily product is obtained which is distilled at 153-156"C/9mbar whose NMR and MS analyses correspond to those of the desired compound. EXAMPLE 9-Svnthesis of 4-methoxy phenol

Analogously to what described in Example 5, a mixture of 10.0g (60mmol) of 1-(4- methoxyρhenyl)-1-proρanone, 15 ml of dichloromethane, 6.1g (130mmol) of 95% formic acid is reacted with 8.25 g (85mmol) of 35% hydrogen peroxide. After treatment of the organic solution as described in Example 5, 0.16g (O.δmmol) of 98% hydrated tetrabutylammonium chloride are added to the organic solution and the mixture thus obtained is reacted with 46ml of 4M sodium hydroxide. After an analogous treatment to that described in example 5, 5.3g of a product are obtained which, after crystallization from petroleum ether has m.p. 54-56°C whose NMR and MS correspond to those of the desired compound. EXAMPLE 10 Synthesis of 3,4,5-trimethoxy-phenol

Analogously to what described in Example 5, a mixture of 11.3g (50 mmol) of 1- (3,4,5-trimethoxy-phenyl)-1-propanone, 15 ml of dichloromethane, 5.5g (110 mmol) of 95% formic acid is reacted with 7.35g (75mmol) of 35% hydrogen peroxide.

After treatment of the organic solution as described in Example 5, 0.12 g (0.4mmol) of hydrated tetrabutylammonium chloride are added to the organic solution and the mixture thus obtained is reacted with 32 ml of 4M sodium hydroxide. After an analogous treatment to that described in example 5, 1.5 g of a product are obtained that after crystallisation from toluene has m.p. = 146-148°C whose NMR and MS analyses correspond to those of the desired compound. EXAMPLE 11. Synthesis of 3,4-methylendioxy-phenol

A mixture of 17.7g (100 mmol) of 1-(1 ,3benzodioxol-5-yl)-1-propanoπe, 26 ml of dichloromethane, 22.5 g (220mmol) of 98% acetic anhydride and 0.42g (2mmol) of monohydrated paratoluensulfonic acid are heated to 40°C, 14 g (140mmol) of 5 hydrogen peroxide are then slowly added.

Once the hydrogen peroxide is completed the mixture is heated to the reflux temperature, afterwards it is cooled and the phases are separated. The aqueous phase was treated with 50 ml of dichloromethane and with 37% hydrochloric acid up to a pH value of about 1. The organic phase was washed

10 twice with water and dried on anhydrous sodium sulphate. After filtration the organic phase is evaporated under vacuum at 30°C/24mbar, thereby obtaining 4.4g of a product which after crystallisation form cyclohexane/dichloromethane has m.p.=63-65°C whose NMR and MS correspond to those of the desired product. EXAMPLE 12. Synthesis of 3,4-mβlhylendioxy-phenol

15 A mixture of 17.7g (lOOmmol) of 1-(1 ,3-benzodioxol-5-yl)-1-propanone, 50 ml of dichloromethane, 33.0g (220mmol) of 97% phthalic anhydride and 0.42g (2mmol) of monohydrated p-toluensulfonic acid are heated to 40°C, then 14.0g (140mmol) of 35% hydrogen peroxide. Once said addition is completed the reaction mixture is heated under reflux for 6

20 hours.

The reaction mixture is cooled and unreacted phthalic anhydride is filtered and the organic solution obtained is treated as reported in Example 11 , utilising the same amounts of reactants. 4.3g of a product are obtained which, after crystallisation of cyclohexane/dichloromethane, has m.p =63-65°C, whose NMR and MS analyses

25 correspond to those of the desired compound.

EXAMPLE 13 Synthesis of 3,4-methylenedioxy phenol

A mixture of 17.7g (lOOmmol) of 1-(1 ,3-benzodioxol-5-yl)-1-propanone, 50 ml of dichloromethane, 21.4g (218 mmol) of maleic anhydride and 0.42g (2mmol) of monohydrated p-toluensulfonic acid are heated to 40°C, then 14.0g (140mmol) of

30 35% hydrogen peroxide are slowly added.

Once the addition is completed the mixture is heated under reflux for 6 hours, afterwards it is cooled and treated as described in example 11 with the same amounts of reactants.

6.3g of a products are obtained which after crystallisation from cyclohexane/dichloromethane has a m.p.=63-65°C, whose NMR and MS analyses correspond to those of the desired product. EXAMPLE 14 Synthesis of 3,4-methylendioxy phenol

A mixture of 17,7g (lOOmmol) of 1-(1 ,3-benzodioxol-5-yl)-1-propanone and 30 ml of dichloromethane are heated to 40°C; then a solution of 40,0g (122mmol) of phtalimido-peroxy hexanoic acid (P.A.P. from Solvay) (title 84.7%w/w) in 100 ml of dichloromethaneare added slowly. Once the addition is completed the mixture is heated to reflux for 10 hours .

Then it is cooled and treated as described in example 11 with suitable amounts of reactants.

6.4 g of a product are obtained which after crystallisation from cyclohexane/dichloromethane has m.p. 64-65°C and whose NMR and MS analyses correspond to those of the desired products.

Claims

1. Process for preparing an alkoxy- and aryloxy- phenol of formula (III)

(III) where Xi and X₂, equal or different, are linear or branched d-Cβ alkyl, Cβ-Cι₀ aryl unsubstituted or substituted with Ci-Cs alkyl, with trifluoromethyl or with halogen, or (OX-ι)n and (OX₂)m, taken together, correspond to the O-T-O group, where T is CHa, CH₂CH₂ or C(Me)₂; n and m are 0, 1 or 2 with the condition that when n=m they are always different from 0, comprising the following stages: a) oxidation of the compound of formula (I)

(1)

(with a peracid in an inert organic solvent to give the corresponding ester of formula (II)); where Xi, X₂, n, m and R is a linear or branched C₂-Cβ alkyl or cycloalkyl b) hydrolysis of the ester of formula (II) to give the corresponding phenol of formula (III).

2. Process as claimed in claim 1 , wherein X_ and X₂ are C₁-C₄ alkyl.

3. Process as claimed in any one of claims 1 or 2, wherein said O-T-O group is CH₂.

4. Process as claimed in any one of claims 1-3, characterised in that R is C₂-C₃ alkyl.

5. Process as claimed in any one of claims 1-5, characterised in that Xi and X₂ are C_ aryl unsubstituted or substituted with C₁-C₂ alkyl.

6. Process as claimed in claim 4, characterised in that R is ethyl.

7. Process as claimed in any one of claims 1-6, characterised in that in the oxidation reaction of stage (a) peracids either preformed or prepared in situ are used chosen from the group consisting of performic, peracetic, permaleic, perbenzoic and perphthalic acids.

8. Process as claimed in any one of claims 1-7, characterised in that said peracid is performic acid prepared in situ by reacting formic acid with hydrogen peroxide.

9. Process as claimed in claim 8 characterised in that the quantity of acid used is between 1.5 and 8 equivalents per mole of ketone.

10. Process as claimed in claim 9, characterised in that said quantity of acid is between 2 and 5 equivalents per mole of ketone.

11. Process as claimed in any one of claims 8-10, characterised in that the quantity of hydrogen peroxide used is between 1 and 6 equivalents per mole of ketone.

12. Process as claimed in claim 11 , characterised in that said quantity of hydrogen peroxide used is between 1.2 and 3 equivalents per mole of ketone.

13. Process as claimed in any one of claims 1-12, characterised in that the 5 reaction is conducted in a solvent immiscible with water and able to dissolve both the ketones of formula (I) and the carboxylic acid or the corresponding peracid.

14. Process as claimed in any one of claims 1-13, wherein said solvent is chosen from pentane, hexane, heptane, octane and their mixtures, dichloromethane, chloromethane, carbon tetrachloride and dichloroethane.

10 15. Process as claimed in claim 14, characterised in that said solvent is chlorinated.

16. Process as claimed in claim 15, characterised in that said solvent is dichloromethane.

17. Process as claimed in any one of claims 1-16, characterised in that the volume 15 of solvent per mole of the ketone of formula (I) used in stage (a) is between 0.05 litres and 1.5 litres.

18. Process as claimed in claim 17, characterised in that said volume is between 0.2 litres and 0.5 litres.

19. Process as claimed in any one of claims 8-18, characterised in that said 20 hydrogen peroxide nas a concentration oetween 30 and 35% (w/v).

20. Process as claimed in any one of claims 8-19, characterised in that the formic acid has a concentration greater than 80% (w/w).

21. Process as claimed in claim 20 characterised in that the formic acid concentration is greater than 85% (w/w).

25 22. Process as claimed in any one of claims 1-21 , characterised in that the oxidation reaction is conducted at a temperature between 20° and 80°C.

23. Process as claimed in claim 22, characterised in that said temperature is between 30 and 50°C.

24. Process as claimed in claim 23, characterised in that said temperature is 30 between 40 and 50°C.

25. Process as claimed in any one of claims 1-24, characterised in that the hydrolysis reaction of stage (b) is conducted in a basic or acidic environment.

26. Process as claimed in any one of claims 1-25, characterised in that in stage (b) the same inert solvent is used as is used in the reaction of stage (a).

27. Process as claimed in claim 26, characterised in that the same reaction mixture derived from stage (a) is used after removing the aqueous phase.

28. Process as claimed in claim 25, characterised in that the hydrolysis reaction in a basic environment is conducted in the presence of a phase transfer catalyst.

29. Process as claimed in claim 28, characterised in that said catalyst is tetrabutylammonium chloride or Aliquat 360.

30. Process as claimed in any one of claims 28 or 29, characterised in that said phase transfer catalyst is preferably added in a molar ratio between 1/20 and 1/90 per mole of ester of formula (II).

31. Process as claimed in claim 29, characterised in that said molar ratio is between 1/40 and 1/80.

32. Process as claimed in claim 25, characterised in that said reaction is conducted in an acidic environment in a C C-io alcoholic solvent.

33. Process as claimed in claim 32, characterised in that said alcohol is a C₁-C₃ alcohol.

34. Process as claimed in claim 33, characterised in that said alcohol is methanol.

35. Process as claimed in any one of claims 25, 28-34, characterised in that the hydrolysis reaction is conducted at a temperature between 30 and 60°C.

36. Process as claimed in claim 35, characterised in that the reaction is conducted at 40°C.

37. Process as claimed in any one of claims 25, 27-36, characterised in that the separation of the alkyloxy- or the aryloxy- phenol of formula (III) derived from the acid hydrolysis, in particular conducted with sulphuric acid, is conducted with a procedure comprising the following steps:

A) the methanol is evaporated under reduced pressure;

B) the remainder is re-dissolved with methylene chloride and a 2M solution of sodium hydroxide is added; the organic phase containing the ketone and the unreacted ester is removed,

C) the aqueous phase containing the sodium salt of the phenol of formula (III) is acidified with organic mineral acid, preferably 37% HCI, to release the alkyloxy- or the aryloxy-phenol of formula (III) which is extracted with methylene chloride,

D) the methylene chloride is evaporated to obtain a residue which is then distilled and/or crystallised to obtain the alkyloxy- or the aryloxy-phenol.

38. Process as claimed in any one of claims 25-27, characterised in that the alkyloxy- or the aryloxy-phenol of formula (III) derived from the basic hydrolysis is separated from the reaction mixture conducted in stage (b) with a procedure comprising the following operative steps:

A) the 2 phases of the reaction mixture are separated; the organic phase containing the unreacted ketone, the non-hydrolysed ester and possibly the catalyst is removed,

B') the aqueous phase containing the sodium salt of the alkyloxy- or aryloxy- phenol of formula (III) is acidified with a strong mineral acid, preferably 37% HCI, to release the corresponding phenolic derivative which is extracted with methylene chloride, C) the methylene chloride is evaporated to obtain a residue which is then distilled and/or crystallised to obtain the alkyloxy- or the aryloxy-phenol derivative of formula (III).

39. Process as claimed in any one of claims 37 or 38, characterised in that the unreacted ketone derived from hydrolysis under acid catalysis or under basic catalysis is recycled in stage (a).

40. Process as claimed in claim 39, characterised in that if the reaction mixture is derived from acid hydrolysis, the organic phase removed from stage (B) of claim

37 is recycled.

41. Process as claimed in claim 39, characterised in that if the reaction mixture is derived from basic hydrolysis, the organic phase removed from stage (A) of claim

38 is used.